1. A 45-year-old CKD 5 male patient on HD secondary unknown kidney disease received a suitable kidney offer from his mother. He had a history of DVT and PE. He is kept on warfarin with INR 3.3
- How do you manage this case?
- Would your management differ if he had recurrent PE despite the anticoagulation?
- Would you manage him differently if he was on newer anticoagulation drugs called dabigatran, rivaroxaban and apixaban?
The management plan focusses on identifying the cause of procoagulant state….It could be related to a primary renal disease like membranous nephropathy in which case, I will check anti PLA2R antibody levels (as kidney biopsy in not possible now due to shrunken kidneys).. The procoagulant state can be related to other thrombophilia which are protein C, protein S deficiency, anti thrombin III deficiency, homocysteine measurement, APLA, anti cardiolipin antibody and beta 2 microglobulin levels… Hematologist role needs to be opined ….
Regarding his anticoagulation, he is on warfarin…It should be stopped 5 days before surgery and bridged with LMWH which should be stopped 12 hours before transplantation…In view of major unprovoked thromboembolic episode in the past , anticoagulation needs to be restarted as early as possible in the post operative period….
If the patient had recurrent PE despite anticoagulation, I would look into the history of regular medication compliance. I would also look into the history any drug interaction with warfarin which will reduce its effectiveness….I would also look into the food drug interaction list which causes reduced anticoagulation…
Other factors related to transplant include high hemoglobin, dehydration and presence of thrombophilic medications like sirolimus….
As there is recurrent PE I will involve the vascular surgeon to consider of IVC filter…
NOAC like dabigatran, rivaroxaban and apixaban are attractive drugs because they offer predictable anticoagulant activity with less drug drug and drug food interactions compared with Vit K antagonists…Dabigatran and Rivoroxaban are renally excreted and their dose needs to be reduced in azotaemia…Apixaban can be given in renal failure with no dose adjustments….
NOAC are required to be stopped 3 days before surgery and bridged with heparin before surgery….
In order to carry out the transplant of this patient, we must use the heparin bridge: in the preoperative period, warfarin should be suspended 5 days before the transplant, subcutaneous low molecular weight heparin should be started 3 days before as a terapeutic dose, being suspended the night before the procedure + the day before the transplant, the prothrombin time should be measured and, if INR > 1.5, therapy with vitamin K or fresh plasma should be established until this goal is reached + in the postoperative period, unfractionated heparin and warfarin (same dose as before suspension) should be restarted within 24-48 hours if there are no signs of bleeding
In order to perform the transplant more safely, I would discuss the implantation of an inferior vena cava filter.
And at the same time, he would study the patient’s thrombogenic factors, such as: antiphospholipid antibodies, HIV, cancer, in addition to studying the coagulation cascade: antithrombin III, Protein C, Protein S, factor V Leiden.
The recommendation is not to transplant a patient using these new anticoagulants. It is preferable to temporarily switch to warfarin and perform the heparin bridge. Only subsequently perform a return of the previous anticoagulant.
45 year old patient with history of DVT and PE
Should be evaluated for the hyper coagulable state disorder including antiphospholipid antibodies , full coagulation profile and factor V Leiden, Protein C, Protein S, antithrombin III .
Regarding warfarin perioperatively, bridging with LMWH before and after Tx procedure (at least 5 days before surgery and restarted 2 days post surgery)
Recurrent PE despite anticoagulation should raise many possibilities such as
1. Hypercoagulable states especially antiphospholipid syndrome, SLE or even cancers
2. Malcompliance or even non compliance to anticoagulation medications .
3. Drug interactions with warfarin
If all factors are exclude and PE recurrence occurred, he may be a candidate for IVC filter .
DOACs should be stopped 2 to 3 days before Tx Surgery and restarted after Tx surgery without the need for bridging with LMWH .
Reversal agents are available for these DOACs (Idarucizumab for dabigatran, and Andexanet alfa for rivaroxaban and apixaban) which can be utilized to reverse their actions rapidly in case of life-threatening severe bleeding
DOACs are safe and effective in Tx recipients as long as GFR remains above 30 ml/min
Drug interactions between CNIs and DOACs should be taken in consideration. And recent studies showed no Drug interactions between Tacrolimus and DOACs .
1- This is a high risk patient going for surgery , hold warfarin for 5 days prior surgery , The American College of Cardiology and American Heart Association recommend heparin bridging with either unfractionated heparin or low-molecular-weight heparin once the INR falls below the therapeutic range (INR < 2.5 in our patient). The LMWH should be stopped 24 hr before the operation and to be restarted 48 hrs post surgery.
2- In case of recurrence of PE despite of coagulation , compliance should be ensured, if patient assure compliance he should have IVC filter. Mean while he should be investigated for thrombophilia including protein C , protein S antiphospholipid and especially that his native disease was unknown. Lupus has to be excluded. Malignancy should have been excluded while evaluating the patient for kidney transplant.
3- ESKD patients have an overall greater risk of thromboembolic events. periprocedural management of NOACs in CKD and ESKD patients has not been well-studied. This patient has a high risk of perioperative thromboembolism if he stops anticoagulation prior to surgery. If the patient receiving DOAC the management would be different as the half life of these medications is longer2-3 days. And INR does not reflect the dosing, Recombinant coagulation factor Xa can be used to reverse rivaroxaban and apixaban if needed, not vitamin K . while dapigatran is contraindicated in ESRD.
References:
Douketis JD, Berger PB, Dunn AS, Jaffer AK, Spyropoulos AC, Becker RC, Ansell J (2008) The perioperative management of antithrombotic therapy: American college of chest physicians evidence-based clinical practice guidelines (8th edition). Chest 133(6 Suppl):299S–339S
Stephen J. Rechenmacher, MD, James C. Fang, M (2015) Bridging Anticoagulation. Journal of American college of cardiology. vol. 66, NO. 12, 1392 – 1403.
Evaluation of thrombophila (deficiency of protein C and S, Antithrombin III and Factor 5 leiden, prothrombin gene mutation, lupus anticoagulant), anti-phospholipid antibodies, and homocysteine levels is required if there is a history of DVT and PE.
Warfarin should be stopped 5 days before the transplant. Check the INR and proceed if it is less than 1.5. If the INR after 5 days is greater than 1.5, inject 1 g of vitamin K per day for few days. Switch to LMWH (1mg/kg) 12-24 hours after transplant.When graft function is stable, warfarin should be resumed.
If there is a history of recurrent PE, an IVC filter needs to be inserted.
DOACs are usually stopped 2–3 days before surgery.
We need to estimate thromboembolic risk versus bleeding risk and to assess the need for anticoagulant interruption and hence bridging anticoagulation if the bleeding risk is high. Thromboembolic risk need through workup to assess the underlying cause and when it had occurred. A temporary inferior vena cava filter is indicated if this patient has a very recent (within the prior three to four weeks) acute VTE.
We need to check INR after stopping warfarin, 5 days prior to operation, and do operation when it is dropped to 1.4 and resume warfarin 12-24 hour after the operation if no risk of bleeding. Subcutaneous LMW heparin should be started 3 days pre surgery and continued post operatively till target INR is reached.(1)
In that case we can adopt kidney transplantation without reversal of warfarin. This was mentioned in one case report of a peritoneal dialysis patient with anti-phospholipid syndrome who was successfully transplanted on warfarin (2).Another report included13 recipients at a single center between 2011 and 2014 who received continued anticoagulation with warfarin with targeted international normalized ratio of 2.0–2.5. only 3 of them developed bleeding in form of hematoma .According to this report, continued warfarin therapy was not associated with a disproportionate amount of adverse events compared to bridging with heparin.(3)
Individuals who interrupt therapy with a direct oral anticoagulant (DOAC) will have a shorter period without anticoagulation than those who interrupt therapy with warfarin, due to the rapid resolution of anticoagulant effect when a DOAC is discontinued preoperatively and the rapid resumption of effect when a DOAC is restarted postoperatively. If the bleeding risk is minimal, omit the dose in day of surgery only for one day. If low/ moderate risk, omit for 2 days before operation and on operation day. If high risk of bleeding, omit 4 days pre , day of surgery and one day after it.(1)
Ref:
1- uptodate
2- David W. Mudge, Scott B. Campbell, Mark Ray, Kidney transplantation without reversal of warfarin, NDT Plus, Volume 3, Issue 2, April 2010, Pages 170–171, https://doi.org/10.1093/ndtplus/sfp150
3- Jonsson, A., & Kayler, L. K. (2015). Kidney transplantation without interruption of warfarin. Clinical Transplantation, 29(8), 665–666. doi:10.1111/ctr.12573
this patient had history of DVT in relatively young age , unknown cause of his kidney disease he needs work up to investigate thrombophilia and consultation of hematology consultant
investigation for thrombophilia includes: factor V Leiden mutation , Protein C and S, antithrombin III, antiphospholipid and anticardiolipin AB.
also anti ds DNA , ANA, for SLE .
Omit warfarin for five days before the procedure (last dose on preoperative day minus 6).
•Preoperative bridging with therapeutic-dose low molecular weight (LMW) heparin starting on preoperative day minus 3, with last dose on the morning of day minus 1.
•Resume warfarin within 24 hours after surgery (usual dose).
•Postoperative bridging on postoperative day 2 or 3, when hemostasis is secured continue for at least four to five days, until the international normalized ratio (INR) is therapeutic.
in case of recurrent PE despite treatment first we have to confirm complaisance to medication , coagulation profile and INR to ensure adequate doses of anticoagulation .
if no other correctable factor
double line anticoagulation may be used with follow up
finally IVC filter might be needed if still having recurrent emboli.
with the use of new oral anticoagulant (NOAC) , they should be stopped 2 days before surgery .
No Bridging with LMWH/ unfractionated heparin in case of NOACs.
Resume dabigatran on postoperative day 2 or 3, when patient is able to take medication by mouth.
Use prophylactic-dose LMW heparin for VTE prophylaxis for the first two to three postoperative days.
James D Douketis, MD, FRCPC, FACP, FCCPGregory YH Lip,Perioperative management of patients receiving anticoagulants.2022 UpToDate,
How do you manage this case?
It has only lately been realised how important thrombophilia is as a risk factor for renal allograft thrombosis and severe acute rejection. In actuality, individuals with thrombophilia account for the bulk of early thrombotic events following kidney transplantation
Assessment for :
Antiphospholipid antibodies
ProteinC , S deficiency
Antithrombin III defiency
Factor V mutation
Hyperhomocysteinemia
Prothrombin gene (G20210A) mutation
There was no association between any of the genetic polymorphisms and venous thrombosis, rejection or graft survival. Screening for genetic and acquired thrombophilic disorders before transplantation remains controversial.
Some programs screen all patients, while others selectively screen high risk of patients with a personal or family history of thrombosis
Duration of anti-coagulant :
Provoked DVT : for 3 months
Unprovoked DVT : longer time 6 months or more may be lifelong if there is genetic predisposition
Before operation : Warfarin is replace with LMWH 5 days before the operation and start anticoagulant D +2 after operation with LMWH
Warfarin can be resumed when the patient regain full ability for eating
Would your management differ if he had recurrent PE despite the anticoagulation?
As high risk patient for thrombosis ( bed ridden – pelvic operations – recurrent thrombosis )
So assessment for compliance on previous anticoagulation
assessment of previous INR levels on marevan therapy
shifting to another anticoagulant
Along with LMWH, a transient IVC filter can be implanted ( before the operation )
Would you manage him differently if he was on newer
anticoagulation drugs called dabigatran, rivaroxaban and apixaban?
considering the expected DOAC and CNI levels, there was no indication of a substantial interaction with apixaban, rivaroxaban, and CNIs. With no VTE events and bleeding episodes occurring at rates comparable to those in published trial data and no bleeding-related mortality, its usage was determined to be safe and effective
It is recognised that more severe renal failure raises the risk of bleeding, including gastrointestinal and cerebral haemorrhages. , there are few safety and effectiveness data with DOACs in patients with a CrCl 30 mL/min This is relevant even if edoxaban and apixaban have CrCl licences down to 15 mL/min
Ref :
Zhang Y, Souverein PC, Gardarsdottir H, van den Ham HA, Maitland-van der Zee AH, de Boer A. Risk of major bleeding among users of direct oral anticoagulants combined with interacting drugs: a population-based nested case-control study. Br J Clin Pharmacol. 2020;86(6):1150-1164.
Leon J, Sabbah L, Aubert O, et al. Efficacy and Safety of Direct Oral Anticoagulants in Kidney Transplantation. Transplantation. 2020;104(12):2625-2631.
The patient has history of pulmonary embolism and DVT, the patient should be evaluated
to detect any underlying hyper-coagulability state ( CBC,peripheral blood smear,PT,aPTT, fibrinogen,protein C and protein S, Antithrombin , PCR for factor V leiden, antiphosholipid antibodies and homocysteine level ).
Pre-operative management and warfarin reversal
Warfarin should be stopped 5 days before surgery to permit gradual normalization of INR with check INR one day before surgery and on the day of surgery and INR less than 1.5 is accepted.
Patients with high risk for thromboembolism may need bridging therapy using low molecular weight heparin for 3 days before surgery and it is discontinued 24 hours before surgery.
Restart of warfarin dose after 12 to 24 hours post-surgery with the dose before, if there is no bleeding risk.
Reassumed Warfarin will take 5 to 10 days to reach its anticoagulant effect, patient with high risk of thromboembolism should receive heparin as bridging in that period.
Low molecular heparin should be stopped at least 24 hours after surgery. In case of high risk of bleeding, the low molecular weight should not re-assumed before 48 hours post-surgery.
Management,if he had recurrent PE despite the anticoagulation:
1.assess patient compliance , the patient takes drug or not , if yes,proper dose or not,
2.If the patient takes Warfarin,check INR,ask about drug interaction(Rifampcin,phenytoin,increased vitamin K intake
3.Search for underlying condition(cancer,vasculitis , antiphospholipid syndrome)
Would you manage him differently if he was on newer anticoagulation drugs called dabigatran, rivaroxaban and apixaban?.
Omit for one to two days before the procedure.No bridging.Resume the drug one to two days after procedure according to bleeding risk.
Therapy with a direct oral anticoagulant (DOAC) will have a shorter period without anticoagulation than those who interrupt therapy with warfarin, due to the rapid resolution of anticoagulant effect when a DOAC is discontinued preoperatively and the rapid resumption of effect when a DOAC is restarted postoperatively..
hematological evaluation: patient with a history of DVT and pulmonary embolism needs to be screened regarding the underlying cause. thrombophilia screen including protein c, protein s, antithrombin III, factor V Leiden, lupus anticoagulant, and anticardiolipin.
vascular evaluation is also needed regarding aortoiliac blood vessels which are the site of anastomosis using CT or MRI angiography after vascular consultation.
cardiological evaluation and pulmonary hypertension are needed as severe pulmonary hypertension consider an absolute contraindication for a kidney transplant.
for warfarin: stopped 5 days before the operation then heparin bridging is needed and can be stopped 12-24h before the operation to be resumed postoperatively in the 1st 24h and after reviewing the patient and the drains. switching again to warfarin usually awaited in the 1st 2w to 1m especially if a biopsy was expected to be needed. warfarin dose should be decreased than the dose the patient used to take before the operation because of the drug-drug interaction between tacrolimus and warfarin.
the underlying cause of recurrent PE should be diagnosed and proper management should be discussed with the patient which may be caused by poor compliance or drug-drug interaction
newer anticoagulants are safe and effective options that can be used in kidney transplant recipients. they can be stopped 2 days preoperative without the need for bridging.
post-operative there is a drug interaction with cyclosporin so,its safer to be used with tacrolimus than cyclosporin
References:
1) Chadban SJ, Ahn C, Axelrod DA, Foster BJ, Kasiske BL, Kher V, Kumar D, Oberbauer R, Pascual J, Pilmore HL, Rodrigue JR, Segev DL, Sheerin NS, Tinckam KJ, Wong G, Knoll GA. KDIGO Clinical Practice Guideline on the Evaluation and Management of Candidates for Kidney Transplantation. Transplantation. 2020 Apr;104(4S1 Suppl 1):S11-S103. doi: 10.1097/TP.0000000000003136. PMID: 32301874.
2) Schulman S. How I treat recurrent venous thromboembolism in patients receiving anticoagulant therapy. Blood. 2017 Jun 22;129(25):3285-3293. doi: 10.1182/blood-2017-03-742304. Epub 2017 May 8. PMID: 28483766.
3) Farge D, Debourdeau P, Beckers M, Baglin C, Bauersachs RM, Brenner B, Brilhante D, Falanga A, Gerotzafias GT, Haim N, Kakkar AK, Khorana AA, Lecumberri R, Mandala M, Marty M, Monreal M, Mousa SA, Noble S, Pabinger I, Prandoni P, Prins MH, Qari MH, Streiff MB, Syrigos K, Bounameaux H, Büller HR. International clinical practice guidelines for the treatment and prophylaxis of venous thromboembolism in patients with cancer. J Thromb Haemost. 2013 Jan;11(1):56-70. doi: 10.1111/jth.12070. PMID: 23217107.
4) Chintalacheruvu LM, Bhatty O, Andukuri VG. Dual Anticoagulation in Recurrent Thromboembolic Events with Failure of Monotherapy: A Novel Approach. Cureus. 2017 Jul 7;9(7):e1444. doi: 10.7759/cureus.1444. PMID: 28924530; PMCID: PMC5589500.
5) Jain N, Reilly RF. Clinical Pharmacology of Oral Anticoagulants in Patients with Kidney Disease. Clin J Am Soc Nephrol. 2019 Feb 7;14(2):278-287. doi: 10.2215/CJN.02170218. Epub 2018 May 25. Erratum in: Clin J Am Soc Nephrol. 2019 May 7;14(5):750. PMID: 29802125; PMCID: PMC6390909.
6) Rimsans J, Sylvester K, Kim M, Connors JM, Gabardi S. A Review of Direct-acting Oral Anticoagulants and Their Use in Solid Organ Transplantation. Transplantation. 2022 Jun 1. doi: 10.1097/TP.0000000000004195. Epub ahead of print. PMID: 35642975.
7) Zakko J, Ganapathi AM, Whitson BA, Mokadam NA, Henn MC, Lampert B, Kahwash R, Franco V, Haas G, Emani S, Hasan A, Vallakati A. Safety of direct oral anticoagulants in solid organ transplant recipients: A meta-analysis. Clin Transplant. 2022 Mar;36(3):e14513. doi: 10.1111/ctr.14513. Epub 2021 Oct 30. PMID: 34655500.
8) Lam E, Bashir B, Chaballa M, Kraft WK. Drug interactions between direct-acting oral anticoagulants and calcineurin inhibitors during solid organ transplantation: considerations for therapy. Expert Rev Clin Pharmacol. 2019 Aug;12(8):781-790. doi: 10.1080/17512433.2019.1637733. Epub 2019 Jul 4. PMID: 31242782; PMCID: PMC6656586.
9) Bixby AL, Lichvar AB, Salerno D, Park JM. Use of direct-acting oral anticoagulants in solid organ transplantation: A systematic review. Pharmacotherapy. 2021 Jan;41(1):28-43. doi: 10.1002/phar.2485. Epub 2020 Dec 24. PMID: 33155327.
Patient on warfarin therapy.
Patient history should be reviewed, to determine the cause of thrombosis, where it was
provoked on no provoked factors, inherited thrombophilia or anti-phospholipid syndrome.
So screening for thrombophilia risk ,antiphospholipid antibody screening, ANA .
Echocardiogram is done for him.
Patient will continue his medication as there’s more experience with warfarin than
DOACS.
Assess bleeding risk is also needed, which depended on the type of operation and
patient characters.
HAS BLED score can be used to stratify the patient bleeding risk, with a score above
three denotes a high risk of bleeding .(1)
Those with a high risk of bleeding will benefit of suspension of the anticoagulant before
the surgical procedure, where’s those with high risk of thromboembolism, a
bridging approach can be used, with a low molecular weight heparin.
This bridging approach is advised by American College of surgery .
Warfarin tablets is stopped five days before the surgery and the low molecular heparin
started at low dose ,matching patient glomerular filtration rate , it is started three days
before the operation .
The International normalization rate is checked two days before the operation, if the
result is more than one point five then vitamin k is given in a dose of one or two
milligram.
The discontinuation of the low molecular weight heparin is done , twenty -four hours
before the operation .
The postoperative warfarin is restarted twelve to twenty -four hours, whereas the
heparin is restarted forty -eight to seventy- two hours post-surgery.
would your management differ if he had recurrent PE despite the anticoagulation?
IVC filter should be used.
The DOACs have lower inter- and intrapatient variability.
much shorter half-lives.
nd less known drug-drug and drug-food interactions .
as compared to warfarin.
standardized dosing recommendations and a wide therapeutic range, permitting their
use without routine drug monitoring.
Despite these demonstrated benefits, the use of DOACs has not gained uniform
acceptance because of lack of supportive data in special patient populations, including
recipients of solid organ transplants .(2)
References:
1- Hau HM, Eckert M, Laudi S, Völker MT, Stehr S, Rademacher S, Seehofer D, Sucher
R, Piegeler T, Jahn N. Predictive Value of HAS-BLED Score Regarding Bleeding Events
and Graft Survival following Renal Transplantation. J Clin Med. 2022 Jul 12:11(14):4025.
2- David M. Salerno,1 Demetra Tsapepas et al. Direct oral anticoagulant considerations
in solid organ transplantation: A review. Clin Transplant. 2017 Jan; 31(1):
10.1111/ctr.12873.
1-How do you manage this case?
evaluation of this recipient details history needed about the cause of CKD and the cause of DVTA and PE, family history of clotting disorder, and need to go back to the history of DVT is provoked if unprovoked need thrombophilia screening such as factor 5 Leiden and prothrombin gene mutation, which account for 50 to 60% of cases other thrombophilia screening include protein S and C deficiency, antithrombin 3 deficiency, ANA and anti-dsDNA, lupus anticoagulant antibodies antiphospholipid abs.
preoperative the warfarin should be held 5to 7days before the surgery and start heparin and hold 12 hours preoperative and resume 48 hours postoperative
Q1_ the most important part in management is identification of underlying cause of DVT and ESKD of the current case.
_ Screening for inherited and aquirred thrombophilia as follows: (protein C and S defficiency , anti thrombin III defficiency, factor V Leiden mutation ) and lupus serology (ANA, anti dsDNA) , screening for anti phospholipid syndrome as (lupus anticoagulant, anti cardiolipin and anti beta 2 glycoprotein antibodies).
_ presence of any of aboverntioned causes of thrombophilia make it essential to use life long thromboprophylaxis.
While absence of predisposing factors makes it sufficient to give prophylaxis for 3_6 months post thrombotic event.
_ warfarin is the most commonly used oral anti coagulant , must be stopped before tranpslant operation by 5_7 days and bridge this gap by LMWH that must be stopped 12 h before operation and resumed agian 24_48 h after transplant operation.
Q2_ occurrence of recurrent thrombosis despite anticoagulation requires :
_ ensure that the patient is complaint to anti coagulant therapy and target INR 2_3.
_ may use IVC filter to prevent pulmonary embolism .
Q3_ as regard direct oral anti coagulants;
_ many reports concluded that their effecicay is not inferior to warfarin
_ they have the advantage that no need for frequent monitoring with INR.
_ they also has no drug _drug interactions as the case with warfarin that has poor oral bioavailability.
_ however, they are not recommended in both lower GFR than 30 mil/min/m2 and also in case of anti phospho lipid syndrome. And should be replaced by warfarin in such conditions.
This patient has renal failure of unknown etiology and DVT- PE,
History: should involve any family history of same condition.
Weather the DVT is provoked or not provoked.
Any history to suggest SLE, APA and malignancy.
Investigation: directed to determine the underlying condition.
ANA , Anti dsDNA , lupus anticoagulant ,anti cardiolipn antibody, protein S, protein C, anti-thrombin iii, factor 5 leiden, pro thrombin gene mutation, searching for malignancy.
As kidney transplant recipient are at high risk for thromboembolic phenomena. This patient will need anticoagulation. We have to balance between the risk of bleeding and risk of recurrence of DVT. Risk of bleeding is assessed by HAS-BLED scoring system. Duration will depend on underlying cause, provoked or not provoked. If DVT is provoked and the underlying cause is known and treatable then duration of 3 -6 month treatment is enough. But if cause is unknown, or it is persistent such as APA or AF then the duration of anticoagulation will be lifelong.
Five days before operation warfarin should be stopped and converted to LMWH or unfractionated heparin.LMWH is stopped 24 hour before operation, iv unfractionated heparin can be stopped 6 hours before operation.
Before operation INR level should be less than 1.4 if is more than this vitamin K amp may be needed to correct the INR.
Post operatively heparin as anticoagulant restarted after 24 hour.
Patient kept on heparin until oral intake is resumed. DAOA are safe drug in transplanted patient with no drug-drug interaction.
Q2
If this patient had recurrence PE inspiteof anticoagulation, at first I have to be sure about adherence to medication, then adequacy of anticoagulation (INR level) as warfarin has high drug-drug interaction. If above factors excluded then I will consult the cardiologist for placement of inferior cava filter.
Q3
Direct-acting oral anticoagulant (DOAC) use is increasing progressively because of proved efficacy when compared to warfarin treatment. Studies prove superiority or at least non inferiority of DOAC in comparison to warfarin. Kdigo recommend not transplant patient while he is on DOAC unless there is expertise in dealing with these agent or there is antidote availability for DOAC (Idarucizumab for dabigatran, and Andexanet for rivaroxaban and apixaban).Therefore these patient should shifted to another anticoagulant in preoperative period. Data on safety of DOAC is limited. Solid-organ transplantation is considered a high-bleed risk surgical procedure; On the other hand the high incidence of VTE post-transplant about 8%, therefore careful management is needed. DOAC can be stopped 24hour before operation. The studies report the safety of DOAC in kidney transplantation and lowest side effect was associated with a pixaban. Regarding the interaction of these drugs with CNI, there is no significant interaction.
reffrences
1)Rimsans, Jessica PharmD, BCPS1; Sylvester, Katelyn PharmD, BCPS, CACP1; Kim, Miae PharmD, MS, BCPS2; Connors, Jean M. MD3,4; Gabardi, Steven PharmD, BCPS4
A Review of Direct-acting Oral Anticoagulants and Their Use in Solid Organ Transplantation, 2022 Nov 1;106(11):2143-2154. doi: 10.1097/TP.0000000000004195. Epub 2022 Jun 1.
Pt should be investigated for the cause of VTE (thrombophilia screen should be sent )prior to transplantation
Diagnosis of the cause will help in choosing which anticoagulant either DOACs or warfarin
If recurrent PE we should assess pulmonary function tests and pulmonologist opinion regarding preoperative assesssment and may consider IVC filter to prevent further PE episodes
regarding management if he is on warfarin we should do bridging with heparin prior to surgery but if DOAC should be stopped 48 hrs before kidney transplantation
How do you manage this case?
Our index case has unknown cause of primary kidney disease, additionally he has DVT and PE. We need a full history (including a family history)and thorough physical examination as he may have a disease causing the renal failure and the thrombo-embolic events such as SLE , antiphospholipid syndrome , membranous nephropathy or an underlying malignancy.
We need to identify whether the VTE was provoked or unprovoked and why warfarin is being used as an anticoagulant. DOACs are now the preferable line of treatment in VTE. However, warfarin is still the first line of treatment in antiphospholipid syndrome.
In provoked VTE a 3 month treatment with DOAC is needed, but if unprovoked a thrombophilia screen may be warranted and the duration of anticoagulation may be lifelong especially if the thromboembolic events were recurrent.
A risk assessment should be done to predict recurrence post-transplant as this will affect the graft function. Bridging therapy with LMWH is required if the patient is on warfarin. So, warfarin is stopped 5 days prior to surgery and replaced by LMWH which is stopped 1 day before surgery. Both LMWH and warfarin are resumed 48-72 hours after surgery when hemostasis is secured.
Would your management differ if he had recurrent PE despite the anticoagulation?
Recurrent VTEs necessitates lifelong anticoagulation. If VTEs occur despite receiving an anticoagulant, this represents anticoagulation failure of that agent. So, if the patient was on Rivaroxiban or Apixiban, we can shift him to Dabigatran or warfarin and the reverse is wright. However, it is mandatory to check the patient compliance and drug interactions first, and if on warfarin , we need to check that his INR is within target. Moreover, a thrombophilia screen need to be carried in liaise with the hematology team.
Prior to transplantation and to prevent graft thrombosis, temporary IVC filter can be inserted coupled with LMWH. The filter can be removed later once oral anticoagulants were resumed.
Would you manage him differently if he was on newer anticoagulation drugs called dabigatran, rivaroxaban and apixaban?
The newer oral anticoagulants (DOACs) have been used safely in VTE and for secondary prevention of stroke with AF. However, anticoagulation in renal patients presents a dilemma because of increased risk of bleeding and thrombosis in these patients. CKD with eGFR< 30 were excluded from most trials due to increased bleeding risks and warfarin is still the drug of choice despite the increased risk of skin necrosis and calciphylaxis in uremic patients on long dialysis . Only Apixiban has been used in some trials and showed equivalent efficacy to warfarin for prevention of thromboembolism on long-term dialysis patients with AF with lower bleeding risk scores. However, data are still conflicting.
Reversal agents are available for the DOACs (Idarucizumab for dabigatran, and Andexanet for rivaroxaban and apixaban). They can reverse their actions in case of life-threatening severe bleeding.
If on DOACs, they need to be stopped 48 hours prior to transplantation surgery, no bridging anticoagulation with LMWH is required due to their rapid onset of action. They are safe with TAC based regimen. However, interaction between DOAC and cyclosporine is reported.
References:
1) Chadban SJ, Ahn C, Axelrod DA, Foster BJ, Kasiske BL, Kher V, Kumar D, Oberbauer R, Pascual J, Pilmore HL, Rodrigue JR, Segev DL, Sheerin NS, Tinckam KJ, Wong G, Knoll GA. KDIGO Clinical Practice Guideline on the Evaluation and Management of Candidates for Kidney Transplantation. Transplantation. 2020 Apr;104(4S1 Suppl 1):S11-S103.
2) Rimsans J, Sylvester K, Kim M, Connors JM, Gabardi S. A Review of Direct-acting Oral Anticoagulants and Their Use in Solid Organ Transplantation. Transplantation. 2022 Jun 1.
3) Lam E, Bashir B, Chaballa M, Kraft WK. Drug interactions between direct-acting oral anticoagulants and calcineurin inhibitors during solid organ transplantation: considerations for therapy. Expert Rev Clin Pharmacol. 2019 Aug;12(8):781-790
1- He should be investigated for Hereditary and acquired causes of hypercoagulable states that can predispose patients to thromboembolic diseases, such as protein C or S deficiency, the presence of factor V Leiden mutation, anti-phospholipid antibody, lupus, shortened activated partial thromboplastin time, anti-thrombin III deficiency, prothrombin 20210A gene mutation, and others. Other point of particular importance is the drug metabolism (esp. CNI) with warfarin therapy. Attention should be made with therapeutic level of these medications with warfarin as well as warfarin level with CNI.
2- Yes, he will require IVC filter insertion.
3- Several analyses showed Our results show that both rivaroxaban and apixaban are safe and efficient oral anticoagulant drugs in renal transplant patients.
Basic-Jukic N, Furic-Cunko V, Juric I. Novel Oral Anticoagulants in Renal Transplant Recipients: A Retrospective Cohort Study. Pril (Makedon Akad Nauk Umet Odd Med Nauki). 2020 Sep 1;41(2):49-55. doi: 10.2478/prilozi-2020-0032. PMID: 33011699.
Management
It starts by meticulous history taking along with clinical examination regarding the cause of kidney disease (previous biopsy if found) other system affection, smoking , cardiac manifestations, predisposing factors if existed for VTE as bed ridden, drug addiction, or was it unprovoked .History suggesting membranous aetiology should be fulfilled.
Full dialysis history is also mandatory, especially vascular access, is it functioning, presence of previous events or failed former accesses.
Adherence to anticoagulation therapy, drug interactions, meals, timing, follow up coagulation profile schedule.
Full screening for thrombophilia tendency is a must, including lupus anticoagulant,C3,C4 , ANA ,Anti DsDNA, ANCA P&C ,Anticardiolipin IgG ,IgM , protein S ,protein C ,antithrombin III.
Full Doppler on arterial and venous system should be evaluated.
Preoperative shifting to heparin and holding warfarin totally would be recommended to minimize bleeding risk with special attention to platelets. Then bridging therapy can be resumed later on after stabilization of condition post operatively.
If the patient had recurrent pulmonary embolization, IVC filter should be advised according to vascular team consultation. Dual anticoagulation can be discussed after hematology consultation .this patient needs multidisciplinary team approach.
Recent direct oral anticoagulants doesn’t require follow up by coagulation profile, but they may not be suitable for such patient post operatively, hematology and vascular consultation are necessary to determine their efficacy. It is advisable to stop DOAC perioperatively as can result in serious bleeding events with the use of heparin instead.
1)Detail history for differential diagnosis of autoimmune disorders eg SLE / APLS.
2) Investigation : ANA / C3/C4/ Anticardiolipin/ anti coagulant antibody, FBC for anaemic status, ECG to rule out AF.
3) Counseling regarding diet compatible for patient on warfarin.
Recurrent PE : IVC filter insertion.
For DVT with PE in ESRD : Warfarin if preferred. No superiority of DOAC in ESRD.
How do you manage this case?
45 y old male, ESRD of unknown aetiology on HD, on warfarin because of DVT and PE history.
He is planned for kidney transplantation from his mother. MM at least will be 111 or less.
Work up for thrombotic events (provoked or not provoked) –à>> thrombophilia work-up.
History, clinical examination and hematology referral. Rule out malignancy as a risk factor of thrombosis.
Anti-phospholipid syndrome, anti-cardiolipin Abs, Lupus anti-coagulant, anti- B2G IgG, IgM , protein C, protein S , anti-thrombin III deficiency. SLE, membranous nephropathy, nephrotic syndrome. Smoking history and lipid profile.
Warfarin antidote is Vit K.
What is the target INR, why it is 3.3? is it within therapeutic target or higher?
Before kidney TX: Stop warfarin at least 5 days; Bridge with LMWH or UFH (depending on the local policy). Stop heparin 24h before the operation.
Restart heparin post-operatively as soon as possible unless there is bleeding.
The first month post renal transplantation is the riskiest duration for thrombo-embolic events, However the incidence remains high in the first 6 months.
Would your management differ if he had recurrent PE despite the anticoagulation?
Hematology consultation.
Recurrent PE while on anti-coagulation requires further work up that includes:
1- Check compliance to medications.
2- Drug or food interaction with warfarin.
3- Primary cause of thrombosis.
Consider IVC filer. Addition of anti-platelets. Target INR should be higher than the previous target. Or switch warfarin to LMWH.
One Case report demonstrated that dual anticoagulants can be utilized in patients with recurrent VTE who fail single agent therapy (one conventional & one DOAC).
Would you manage him differently if he was on newer anticoagulation drugs called dabigatran, rivaroxaban and apixaban?
Can be stopped 48-72 hours before the operation.
DOAC s don’t require frequent monitor of INR, they have rapid onset of action. However, some of them are contra-indicated with low GFR and not licensed to be used in dialysis patients.
DOACs are not approved in anti-phospholipid syndrome.
DOACs are less effective than warfarin for recurrent thrombosis prevention in patients with APS especially in those with a history of arterial events.
Lower inter and intra-patient variability, so standard doses are usually used.
DOACs don’t need bridging with Heparin.
Can be restarted post-operatively within 48-72 hours (high bleeding risk procedure) unless there is bleeding.
Apixaban and rivaroxaban are metabolized by CYP3A4.
CNIs inhibit p-glycoprotein and CYP 450 3A4.
DOACs can be safely used post RTx without increased risk of bleeding because of absent indirect interaction with CNIs compared to higher risk of bleeding in case of warfarin.
DOACs antidotes: Andexanet for Apixaban & Rivaroxaban
Idarucizumab for Dabigatran
*Data available, we have male patient CKD Vd with unknown cause , Having history of DVT, PE:
1.To manage is case , we have to : 1. take full history . 2. Search for any cause of hypercoagulability so;Thrombophilia profile must br screened which includes: ( protein S, ptn C, factor V leiden PCR , Homocysteine level, antithrombin III, and prothrombin gene mutation. Also, SLE and anti-phospholipid Syndrome must be ruled out by anticardiolipin AB, lupus anticoagulants. 3. Malignancy screening also have to be done. 4. Hematology Consultation. 5. Managing of anticoagulant accordingly before surgery time. 6. Knowing the cause, will guide the recurrence percentage.
*Would your management differ if he had recurrent PE despite the anticoagulation: better to fix IVC filters or use dual anticoagulant.
*Would you manage him differently if he was on newer anticoagulation drugs called dabigatran, rivaroxaban and apixaban?
Only apixaban can be used in GFR less than 30 , but should be stopped 72 hours before surgery, resume it as soon as possible 24hours after surgery.
It is generally agreed that routine testing testing for hypercoagulable disorders (Inheritable thrombophilia and anti-phospholipid Syndrome) in unselected patient with VTE is not warranted.
This is because most patients with VTE, the identification of an inheritable defect does no alter therapeutic or prophylactic anticoagulant managment, and consequently it has not been associated withimproved outcome ( e.g. Mortality or recurrence).
Several trials of patients with unselected VTE reports no difference in recurrence rate in patients with or without inherited thrombophilia , on or off anticoagulations.
warfarine shpuld be stopped 5 days before surgery and should be shifted on LMW heparin which should be stopped 24 hours before surgery.
In case of recurrent PE despite anticoagulation he should be consider for IVC Filter.
Dabigatran, Rivaroxaban and apixaban (DOAC) because of their rapid resolution of anti -coagulation effect when DOAC is discontinued and the rapid resumption of effect when a DOAC is restarted, they should be stopped 2 days before surgery and can be restrted 2 days after surgery.
History of the patient should be taken again so as to find any clue to what caused ESRD in the first place. This will help us to understand any challenges related to outcome of graft and patient.
Since the patient has history of DVT and PE, repeat workup of blood panel, especially BT, clotting time, PT, aPTT is to be done. Special hematology consult needed because of the risk of thromboembolic events in peri-operative or post operative period, or even later.
Hold warfarin 5 days before surgery and start LMWH. INR is to be monitored, it has to come to a level less than 1.5.
If the patient has recurrent PE then anticoagulation is not enough and has to be intensified with hematology consult. Workup for Protein C protein S deficiency may be helpful.
Newer anticoagulation drugs like dabigatran, rivaroxaban and apixaban need to be studied further to apply. However constant INR monitoring requirement is alleviated.
We need to investigate for etiology of thrombophilia and cause of his ESRD which could be contributing to thrombosis Detailed history and physical examination and lab work up including antithrombin, protein S, protein C, factor v Leiden and lupus anticoagulant.
Perioperatively, warfarin to be stopped 5 days before the operation and bridging with LMWH , which can stopped 24 hrs before operation and resumed 2 days after operation..
Use IVC filters.
These drugs to be stopped at least 2-3 days before kidney transplantation. Studies showed that Apixaban has the best side-effect profile and safety .
How do you manage this case?
multidisciplinary team management.
this patient needs to have a haemophilia screen before transplantation to identify the exact cause of his recurrent thrombosis, in addition to the pretransplant workup. the haemophilia screen includes a screen for protein S,C, factor V, Homocysteine level, antithrombin III, and prothrombin gene mutation. Also, anticardiolipin AB, lupus anticoagulants, and screen for malignancy. better to include a haematologist in his work-up. (any hypercoagulable state).
stop warfarin 5 days before surgery with the introduction of heparin which can be stopped 24 hrs before surgery.
prepare FFB and Blood units
anaesthesia and surgical assessment before transplantation
counsel the patient about the high risk of bleeding, perioperative risk, and ICU need.
The patient with H/O PE so he needs a strict respiratory and cardiology assessment.
Would your management differ if he had recurrent PE despite the anticoagulation?
he needs IVC filter and dual anticoagulation example (warfarin + rivaroxaban)
Would you manage him differently if he was on newer anticoagulation drugs called dabigatran, rivaroxaban and apixaban?
these agents have lower risk of bleeding as compared with warfarin. they should be stopped 2 days before surgery and reintroduced 1 -2 days after if no bleeding.
apixaban has less risk of bleeding in ESRD as compared to dabigatran and rivaroxaban
How do you manage this case?
usual work up for kidney transplantation
focus on DVT and PE work up to know the cause ( autoimmune , malegnancy or thrombophilia ) careful family history
consider hematology consultation
need to assess lung function as there is PE before (PFT /CPET)
perioperative consederation regarding beelding need bridge heparin heparin
Would your management differ if he had recurrent PE despite the anticoagulation?
yes may need to increase anticoagulant dose or change to other
extensive search for the cause and treat it also check compliance with medication
may need intravascular filter insertion
Would you manage him differently if he was on newer anticoagulation drugs called dabigatran, rivaroxaban and apixaban?
no need for INR follow up
consider hematology consultation
dose adjusted consederation with early days of operation
1-
I would manage this patient by more assessment of the VTE history. whether it was spontaneous or provoked VTE. , duration , recurrence ..etc.
For the elective operation , warfarin usually is holed for 5 days prior the surgery., i would follow him up with Pt and INR
2- if the patient has history of recurrent VTE, then the possibility of hemophilia is present. thus, I would consult hematologist for evaluation of SLE, APS, protein C and S deficiency.
3- for DOACs, give till 3 days before the surgery.
I- trial to get the etiology of thrombosis and involve a hematologist for this purpose. The diagnosis of the etiology of thrombosis will give me a future assessment of the recurrence and also if any condition needs specific treatment
II- preoperative:
Stop warfarin 5 days prior to the surgery (we need to involve the surgeon and anesthetist for pre-surgical assessment) , monitor INR till become less than 1.5 , start LMWH in the same day of stopping warfarin and stop it 24 hours before the surgery.
Prepare FFP, packed RBCs (washed), Vit K ……just in case of non- predicted uncontrolled bleeding
III- post-operative
Start LMWH 12-24 hour post-operative
Assess the risk of bleeding
If no bleeding resume warfarin with the same dose as prior to the surgery, monitor INR to reach the target 2.5-3.5, and continue warfarin alone indefinitely
The decision is taken by the whole team of transplant especially the surgeon and nephrologist
IV- drug-drug interaction
Warfarin has many drug-drug interaction so we need careful monitoring of INR and drug level of immunosuppressive medications especially CNI ; we need to involve clinical pharmacist and dietitian for this drug interaction
The patient may need IVC filter or use dual anticoagulation
Apixaban the only one approved for eGFR < 30 ml/min
It doesn’t have monitoring test or antidote
It can be stopped 1-2 days before the surgery and restart 1 day after the surgery
Others can be used post transplant and they have advantage that they have less drug-drug interaction than warfarin
Q1
Taking a complete history regarding risk factors for DVT or PE should be done.
A good balance between reducing the risk of DVT/PE and prevention of bleeding should be reached in this patient.
Risk factors are arterial fibrillation, mitral or aortic valve prosthesis, stroke or TIA, diabetes, hypertension, congestive heart failure , and age more than 75 years, immobility. I will hold warfarin 5 days before TX and start LMWH or unfractionated heparin and stop them 24h before surgery and then if there is no bleeding, LMWH will .
start 24 to 48 h after surgery
Q2
Thrombophillia screening should be done by screening for activated protein C(APC) resistance, factor V and prothrombin gene mutations, anticardiolipin antibody, lupus anticoagulant, protein C and S, antithrombin III, and homocysteine level. Complete evaluation for cardiac and pulmonary function is considered with consultation.
Then patient should be on therapeutic dose of LMWH with dose reduction after at least one month and for long-term either LMWH or oral anticoagulants.
Q3
Use of DOACS is avoided in ESKD or patients on HD especially for rivaroxaban and dabigatran. Apixaban seems need more studies.
How do you manage this case?
In the first instance I would like to know the past medical history as why he has DVT (e.g. SLE, Antiphospholipid, Factor V, Homocytseine, Protein C-S, screening for malignancy etc) and I would involve the hematologist. We need to determine the thromboembolic risk and procedural bleeding risk
We should stop warfarin 5 days before the procedure and bridge with Tinzaparin. Tinzaparin should be stopped 24 hours before the procedure. Before the procedure INR should be less than 1.4. Vitamin K should be administered if INR is equal or more than 1.4. LMWH should be restarted 48 hours after the procedure. We have to consider the interaction between Warfarin and immunosuppressant agents after transplant (kidney transplant recipient required approximately 20 % lower warfarin dose).
This patient should be investigated for thrombophilia (e.g. SLE, Antiphospholipid, Factor V, Homocytseine, Protein C-S, screening for malignancy etc). Hematologist should be involved. If the patient has history of recurrent PE, there is an increased risk of recurrence post transplant. This patient should receive life-long Anticoagulation therapy and IVC Filter (if recurrent VTE).
There is no need to monitor INR. Rivaroxaban is associated with major risk of bleeding compared to Apixaban. DOACs should be stopped two-three days before surgery, and 1-2 days after surgery. Bridging therapy wiyh LMWH is not required in case of DOAC
Novel Oral Anticoagulants in Renal Transplant Recipients: A Retrospective Cohort Study
Nikolina Basic-Jukic 1, Vesna Furic-Cunko 1, Ivana Juric 1
Affiliations expand
Handbook of Kidney Transplantation
Edited by
Gabriel M. Danovitch, MD
My management plan will focus on:
Regarding the cause of thromboembolic phenomena: screening for malignancy, APL syndrome, SLE, coagulation factors abnormalities, protein c, protein S deficiency, antithrombin III, homocysteine, fibrinogen, and history of COVID19 infection. Of course, a need for a haematologist’s opinion and help is required.
Regarding anticoagulation: he is on warfarin; this drug should be stopped 5 days pre-op. and LMW heparin should be started with consideration of stopping it 24 hr before transplant surgery and re-initiation as early as possible in the post-op period as the risk of thrombosis recurrence is very high in this period.
Renal transplant recipients have an increased risk of venous thromboembolism, possibly due to impaired fibrinolysis and a persistent hypercoagulable state. A higher rate of recurrence is noticed in patients who stopped oral anticoagulation. Additional risk factors related to transplant itself such as dehydration and IS medications such as sirolimus.1
For this patient, I will check his compliance to OA medications, screening for PT, PTT, and INR, screen for the causes of thrombophilia, keep him on long-term anticoagulation with consideration of interaction with IS medications, evaluation of IVC by angiography to assess the need for IVC filter.
DOACs are particularly attractive because they offer predictable anticoagulant activity at fixed doses with less frequent drug-drug or food-drug interactions compared with the traditionally used vitamin K antagonists and no need for therapeutic drug monitoring. Several RCTs have established their superiority or non-inferiority compared with vitamin K antagonists for preventing thromboembolic events and their safety profile (major bleeding events) in the general population.2
Dabigatran and Rivaroxaban are excreted through kidneys and are associated with higher bleeding risk in ESRD patients compared to warfarin, while apixaban is less likely to be excreted by kidney therefore bleeding risk is lower in ESRD patients.
For this patient, DOACs should be stopped before transplant in a sufficient time to remove the drug from the circulation, and this time will differ according to the GFR; the lower the GFR, the more time required to eliminate the drug. Bridge treatment with unfractionated heparin or LMW heparin needs to be used, and re-initiation of DOACs after surgery as long as there is no bleeding.
References:
# How do you manage this case
Should be involve the other team:
pulmonologist
cardiologist
hematologist
in pre transplantation workup, because this patient is at very high risk.
history and clinical examination for identification the risk of DVT and PE and other factor for VTE
Investigations including:
CXR, ECG, Echocariogram,MPS, Doppler U/S for LL, PFT Anti- cardiolipin, Beta2 glycoprotein, ANA profile, complement C3 and C4,PT, PTT, fibrinogen, anti-thrombin, protein C, protein S, lupus anticoagulant, factor V, leiden.
The warfarin anti-coagulant should be stopped for 5 days pre transplantation, and give LMW heparin, which can be stopped before 24 hours from operation, and then restarted after 2 days.
# Would your management differ if he had recurrent PE despite the anticoagulation?
optimal combination of anticoagulation with minimal bleeding risk.
# Would you manage him differently if he was on newer anticoagulation drugs called dabigatran, rivaroxaban
They have similar effectiveness in the reduction of stroke or systemic embolism. Furthermore, apixaban appears to be associated with a lower risk of major bleeding, whereas rivaroxaban is associated with a higher risk of major bleeding.
# How do you manage this case?
*MDT with hematologist, pulmonologist and cardiologist should be involved in pre transplantation workup, because this patient is at very high risk to develop thrombus(history of DVT, PE, CKD and his will undergo
for major surgary).
Full history and clinical examination for identification the risk of DVT and PE and other factor for VTE
Investigations including routine inv, CXR, ECG, Echocariogram,MPS, Doppler U/S for LL, PFT Anti- cardiolipin, Beta2 glycoprotein, ANA profile, complement C3 and C4,PT, PTT, fibrinogen, anti-thrombin, protein C, protein S, lupus anticoagulant, factor V, leiden
The warfarin anti-coagulant should be stopped for 5 days pre transplantation, and give LMW heparin, which can be stopped before 24 hours from operation, and then restarted after 2 days.
# Would your management differ if he had recurrent PE despite the anticoagulation?
*Dual anticoagulation can be used in patients with recurrent VTE especially when monotherapies have failed them. Caution should be exercised in evaluating the benefits and risks (mainly bleeding) before giving this treatment. Further studies are needed to determine the optimal combination of anticoagulation with minimal bleeding risk.(1,2)
# Would you manage him differently if he was on newer anticoagulation drugs called dabigatran, rivaroxaban and apixaban?
*In the large real-world NVAF cohort, direct comparisons show a favorable bleeding risk profile for dabigatran and apixaban in standard dose, and for apixaban in reduced dose. No differences in effectiveness were found. This study confirms previous indirect DOAC comparisons. Further studies are needed.(3)
References
1. Galioto NJ, Danley DL, Van Maanen RJ. Am Fam Physician. Vol. 83. Accessed; [May;2017 ]. 2011. Recurrent venous thromboembolism; pp. 293–300. [PubMed] [Google Scholar]
2. The management of recurrent VTE in cancer patients receiving therapeutic anticoagulation: the use of dual anticoagulant therapy combined with an IVC filter. Pillai AR, Olujohungbe A, Evans MR, et al. http://journals.lww.com/bloodcoagulation/Abstract/2010/12000/The_management_of_recurrent_VTE_in_cancer_patients.10.aspx. Blood Coagul Fibrinolysis. 2010;21:766–769. [PubMed] [Google Scholar]
3.Jansson M, Själander S, Sjögren V, Renlund H, Norrving B, Själander A. Direct comparisons of effectiveness and safety of treatment with Apixaban, Dabigatran and Rivaroxaban in atrial fibrillation. Thromb Res. 2020 Jan;185:135-141. doi: 10.1016/j.thromres.2019.11.010. Epub 2019 Nov 13. PMID: 31816553.
☆How do you manage this case?
▪︎In this 45-year-old CKD 5 male patient on HD secondary unknown kidney disease who received a suitable kidney offer from his mother and with a history of DVT and PE on warfarin with INR 3.3
▪︎We must assess the thromboembolic events because any thrombotic event may affect graft survival.
▪︎ Details medical (DM or HTN) and family history of similar events.
▪︎ History of injury, obesity or smoking,
▪︎ Exclude APS (antiphospholipid syndrome) either primary or secondary to SLE).
▪︎Check Protein C, Protein S and antithrombin III defeciency
▪︎Then anticoagulation will depend upon the cause.
▪︎The risk assessment should be done to avoid recurrence post transplantation.
▪︎The anticoagulant must be discontinued if the risk of surgical bleeding is high [1]. But, at the same time this pt has very high thromboembolic risk so, we should limit the period without anticoagulation to the shortest possible interval. We can use a bridging agentsuch as LMW Heparin.
▪︎We must stop Warfarin 5 days before surgery.
and Heparin should be stopped a day before surgery and could be restarted 24 hours post transplant.
Would your management differ if he had recurrent PE despite the anticoagulation?
▪︎Management of patients with recurrent thromboembolic events is still a challenging clinical scenario.
▪︎This patient will need standard assessment for thrombophilia and we must rule out hypercoaguable states including APD and malignancies and assess the patient adherence to the anticoagulant drugs.
▪︎Then, adual anticoagulation can be used in this patient but caution should be exercised in evaluating the benefits and risks (mainly bleeding) before giving this treatment. Warfarin and rivaroxaban can be used as a dual treatment [2].
☆Would you manage him differently if he was on newer anticoagulation drugs called dabigatran, rivaroxaban and apixaban?
▪︎The direct oral anticoagulants (DOACs; dabigatran, factor Xa inhibitors [rivaroxaban, apixaban]) have shorter half-lives, making them easier to discontinue and resume rapidly.
▪︎ They have similar effectiveness in the reduction of stroke or systemic embolism. Furthermore, apixaban appears to be associated with a lower risk of major bleeding, whereas rivaroxaban is associated with a higher risk of major bleeding.
▪︎These drugs act differently and there is no need to watch INR and they were developed and approved for use without the need for routine laboratory monitoring [3].
▪︎They must be stopped two days before surgery and can be restarted after1-2 days of surgery.
________________________
Ref:
[1] James D Douketis, et al. Perioperative management of patients receiving anticoagulants
[2] Lakshmi Manogna Chintalacheruvu, et al. Dual .Anticoagulation in RecurrentThromboembolic Events with Failure of Monotherapy: A Novel Approach.
[3] Wayne L. Chandler, et al. Anticoagulation Without Monitoring. American Journal of Clinical Pathology, Volume 140, Issue 5, November 2013, Pages 606–607,
Regarding this 45 years old male with CKD5 on HD due to unknown cause with history of DVT and PE , have suitable kidney offer from his mom ,on warfarin treatment,we first should seek for the cause of his thrombophilia as well as the cause of his ESRD which may be the cause of his thrombosis episode .
So detailed history and physical examination and We assess antithrombin , protein S , protein C, factor v Leiden , lupus anticoagulant.
For peri operative preparation we should stop warfarin 5 days before the operation and bridging with LMWH , which stopped 24 hrs before operation and resumed 48 hrs after transplantation.
It’s best to use IVC filters.
it is recommended that DOACs be stopped at least 48-72 hours prior to kidney transplant patients. Apixaban seems to have the best side-effect and safety profiles in most studies.
Many thanks Dr Khudhur and Dr Essmat,
Let us move to week 3 now.
This is a 45 years old male patient on dialysis , of unknown Kidney disease , receiving a “suitable” offer from his “mother” , He has a history of DVT and PE
Proper and full history and examination of the patient should be done :
-HTN
-Diabetes
-smoking
-PVD
-CAD
-CVD
-BMI
-Any history of rheumatological or immunological symptoms or signs ( Arthralgia , arthritis , orogenital ulcers , malar rash , alopecia )
-history of proteinuria or symptoms of nephrotic syndrome
-Why did he suffer DVT ? unprovoked?
-liver disease
-blood transfusion
-how long has he been on dialysis
-Family history
Investigations including :
-labs : CBC , ALT ,AST ,GGT ,ALP ,bilirubin, blood group , HLA , Virology , bleeding profile
-Solid phase assays-DSA’s by luminex
-ECG , ECHO
-Duplex iliac vessels
If the pulmonary embolism was recurrent :
-Thrombophilia screening : protein S , C , Factor 5 leiden , MTHFR, APL panel.
-Anti coagulation targeting INR 3.5 but no favorable results are anticipated .
-Vascular consultation regarding the possibility of IVC filter prior to RTx Surgery.
warfarin should be stopped 5 days prior to the surgery with LMW heparin used as bridging which is stopped 24 hrs before surgery and then resumed around 48 hrs after RTx hand in hand with LMW heparing till reaching the targeted INR .
-If he was on NOACS then no INR monitoring would be needed , stopping them 24 hrs before surgery ,not preferred after the RTx due to drug drug interaction with CNI’s but if recurrent PE then warfarin is preferred.
Since the patient is on warfarin for the DVT and PE one has to stop warfarin 5days before surgery and be placed on low molecular weight heparin until 24hrs before surgery. The low molecular weight heparin will be initiated 48hrs after surgery
With recurrent PE there will never need to place IVC filter before surgery
With NOACwe will have to withhold it 3days before surgery and start low molecular weight heparin till 24hrs before. Apixaban showed a better safety profile compared to the other NOAC.
Several DOACs have been approved for the prevention of thromboembolic events in atrial fibrillation including apixaban, edoxaban, rivaroxaban (Xa inhibitors), and dabigatran (a thrombin inhibitor).
Regardless of the mechanism of action, DOACs have been shown to be superior to warfarin for thromboembolic prevention and safer in terms of bleeding in patients with AF.
However, this evidence is hard to extrapolate in patients with CKD.
Two forms of protein S are present in plasma: free protein S (40%) and protein S linked to the C4b-binding protein (60%).
Only the free form has functional cofactor activity.
Protein S deficiency may be hereditary or acquired.
It has been associated with a high risk of developing venous thromboembolism especially in young people.
As only the free form of Protein S has the cofactor activity it is only this form that is measured. APC Resistance Assay: Protein C is a naturally occurring inhibitor of blood coagulation, acting on activated factor V and VIII.
The condition whereby a patient’s plasma does not produce the appropriate anticoagulant response to activated protein C (APC) is termed APC resistance.
This is caused by the VQ506 gene mutation which produces factor V Leiden, a factor V molecule which is resistant to cleavage by activated protein C. Factor V Leiden mutation:
The identification of Factor V Leiden mutation is carried out using PCR technology.
This method is used to identify the genotype of the abnormality.
PCR testing is carried out on all samples that have a reduced APCR or have a family history of factor V Leiden.
Prothrombin gene mutation (G-20210-A):
The mutation in the factor II gene (G-20210-A) is in the untranslated portion at start of the gene and is probably part of the regulatory system for the gene.
People carrying the mutation have higher levels of factor II than normal and the increased risk of thrombosis is thought to be a function of this.
Lupus anticoagulant (LA): There is one acquired abnormality which is associated with an increased risk of venous thrombosis.
That is the lupus anticoagulant, so called because it was first described in association with SLE. A lupus anticoagulant is an anti-phospholipid antibody.
Cause of inherited thrombosis is deficiency of proteins in the fibrinolytic system, these proteins break down blood clots once they are formed.
Deficiencies of the fibrinolytic system are very rare and are not usually tested for. Protein C: Protein C is part of the anticoagulant regulatory mechanism.
It is converted to activated protein C (APC) by thrombin in the presence of thrombomodulin.
APC inactivates activated factors V and VIII. Protein C deficiency has been shown to be a risk factor for thrombosis.
Antithrombin: Antithrombin (AT) is a major inhibitor of blood coagulation and is essential for effective heparin therapy.
AT inhibits the coagulation proteases including II a, X a , IX a and XI a. AT deficiency is associated with a high risk of thrombotic disorders.
Free Protein S: Protein S is a vitamin K dependent cofactor for the anticoagulant activity of activated protein C (APC).
Heparin is stopped 4-6 hours before surgery.
Anticoagulation should be discussed with the haematologist who guides the treatment. Thrombophilia screens will not be processed on patients on unfractionated heparin, as heparin interferes with all of the coagulation-based assays of a thrombophilia screen and can cause reduced Anti-thrombin.
Patients on low molecular weight heparin may be tested dependent on the coagulation screen results.
If it is not possible to carry out the thrombophilia screen after warfarin therapy or when patients are on lifelong warfarin a limited number of tests are available but it is important to inform the laboratory of the patient’s therapy.
During warfarin therapy it is not possible to interpret Protein C and S results as these are both vitamin K dependent proteins and are reduced during the treatment.
Many transplant centres prefer not to operate on patient on dual antiplatelet therapy. They wait till one agent is stopped.
It is safe to operate while the patient on aspirin only.
Warfarin is topped 2 days before elective surgery.
For emergency operation warfarin is reversed by vitamin K injection or prothrombin complex concentrates (Beriplex).
Anticoagulation can be continued using unfractionated heparin as it is easier to reverse.
How do you manage this case?
For evaluation and pre-operative management of a patient on anticoagulant the followings should be determined:
1. Determine the Thromboembolic Risk of the Patient.
High risk; AF, prosthetic heart valves and recent VTE.
2. Determine the Procedural Bleeding Risk:
a. to consider the type of surgery.
b. to consider the clinical characteristics of the patient(HTN, abnormal LFT/KFT, stroke, bleeding history or predisposition, labile INR, elderly, drugs and alcohol = HAS-BLED).HAS-BLED score is a reliable predictor of perioperative bleeding1. Each positive item earns 1 point and a HAS-BLED score of >3 indicates a high risk of bleeding.
c. the procedural risk can be divided into:
i. low risk (0-2% two-day risk of major bleeding)
ii. high risk (2% to 4% two-day risk of major bleeding)
3. determine Whether or Not Interrupt Anticoagulation or Antithrombotic Therapy: clinical judgement is imperative and the balance between the risk and benefit of anticoagulation is the right approach to take the decision.
4. Determine Whether or Not Bridging Anticoagulation:
Bridging anticoagulation consists of the substitution of a long-acting anticoagulant (usually with warfarin) for a shorter-acting anticoagulant (usually LMWH) to limit the time of subtherapeutic anticoagulation levels and minimize thromboembolic risk.
Patients with high risk of VTE are more likely to benefit from bridging therapy:
a. patient with mechanical heart valve.
b. Patients with stroke, episode of systemic emboli, or VTE during the last 3 months. Patients presenting with a thromboembolic event after interruption of chronic anticoagulation therapy or those presenting with VTE while on therapeutic anticoagulation.
c. Patients with atrial fibrillation plus additional cardiovascular risk factors (rheumatic valve disease, stroke, or systemic embolism within the last 12 weeks).
d. Patients with recent coronary stenting (within the previous 12 weeks)
Provided the diagnosis of DVT and PE without any information about the underlying, whether provoked or unprovoked, the index patient is a high-risk patient going to kidney transplant operation which carries a high procedural risk(2-4%).
This patient will benefit from bridging therapy: how to bridge? According to American Society of Regional Anesthesia (ASRA)2018 guidelines:
During the preoperative period:
1. Discontinue warfarin five days before surgery. The INR should be less than 1.4 before any neuraxial approach.
2. Three days before surgery, start subcutaneous LMWH or unfractionated heparin (UFH), depending on the renal function of the patient at therapeutic doses.
3. Two days before surgery assess INR, if greater than 1.5 vitamin K can be administered at a dose of 1 to 2 mg.
4. Discontinue LMWH 24 hours before surgery or 4 to 6 hours before surgery if UFH.
During the postoperative period:
1. If the patient is tolerating oral intake, and there are no unexpected surgical issues that would increase bleeding risk, restart warfarin 12 to 24 hours after surgery.
2. If the patient received preoperative bridging therapy (high thromboembolic risk) and underwent a minor surgical procedure, resume LMWH or UFH 24 hours after surgery.
3. If the patient underwent a major surgical procedure, resume LMWH or UFH 48 to 72 hours after surgery.
4. Risk of bleeding and adequacy of homeostasis,should be assessed before the resumption of LMWH or UFH.
Would your management differ if he had recurrent PE despite the anticoagulation?
· If he had recurrent PE, transplant surgery needs to be deferred up to 3 months as the risk of recurrence in the subsequent month can be as high as 40%2.
· Underlying of VTE recurrence should be sought, looking for SLE and APS beside thrombophilia screen.
· Anticoagulation therapy has to be life-long.
Would you manage him differently if he was on newer anticoagulation drugs called dabigatran, rivaroxaban and apixaban?
If being on DOACs, I would manage him differently:
1. Bridging therapy is not indicated in patients on DOACs.
2. The predictable pharmacological effect of DOACs allows a properly timed interruption of anticoagulation therapy before surgery.
3. According to ASRA 2018 GLs; The appropriate timing interruption for patients on DOAC anticoagulation is based on the invasiveness and bleeding risk of the procedure, pharmacokinetic profile of the DOAC, and clinical characteristics of the patient (renal function and liver function).
a. low-risk procedures: DOACs should be held 3 half-life times before the procedure.
b. high-risk procedures: DOACs should be held 5 half-life times before the procedure.
c. less than low bleeding risk procedure: such as a colonoscopy without biopsy, where DOAC therapy may be continued.
d. Betrixaban is a new inhibitor of factor Xa, with many aspects of the clinical use still under study, ASRA (2018) recommends betrixaban interruption at least 72 hours before a neuraxial block. ASRA also recommends at least 5 hours between catheter removal and reinitiation of the drug
e. Rivaroxaban, Apixaban, and Dabigatran:
(i) For high bleeding risk procedures and CrCl>50 ml/min: these drugs should be suspended 48 hours before surgery.
(ii) For high bleeding risk procedures and CrCl< 50 ml/min: these drugs should beinterrupted for four days before surgery.
(iii) For low bleeding risk procedures in patients with CrCl>50 ml/min:rivaroxaban, apixaban, and dabigatran should be interrupted 24 hours before surgery.
(iv) For low bleeding risk procedures in patients with CrCl <50 ml/min: these drugs should be suspended two days before the procedure.
(v) Regardless of renal function, all drugs can be reinitiated at 48 hours for high bleeding risk procedures and 24 hours for low bleeding risk procedures.
Reference
1. Omran H, Bauersachs R, Rübenacker S, Goss F, Hammerstingl C. The HAS-BLED score predicts bleedings during bridging of chronic oral anticoagulation. Results from the national multicentre BNK Online bRiDging REgistRy (BORDER). Thromb Haemost. 2012 Jul;108(1):65-73.
2. Polania Gutierrez JJ, Rocuts KR. Perioperative Anticoagulation Management. [Updated 2022 Jan 26]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2022 Jan-. Available from: https://www.ncbi.nlm.nih.gov/books/NBK557590/
The Evaluation Process of the patient:
1. We need to take more history about the duration of HD, , also important to ask about family history
2. Investigate to know about the cause of kidney disease/ DVT
3. Any associate co mrbidity that might increase risk of DVT and PE( OBESITY, IMMOBILIY, UNCONTROL DM, HTN , HEMATOLOGICAL DISORDERS OR HEART DISEASES)
4.MDT including the Nephrologists, Endocinologist,Surgeons , dietion,Renal Pharmacist, Renal Psychologists.
5. . Consider him as hig risk for DVT/PE before and after transplant
6.Prevention of venous thrombosis After transplant by compression stockings as well as early ambulation. The addition of 5,000 U of unfractionated heparin subcutaneously is appropriate; however, this risk must be balanced against an increased risk for hemorrhagic complications and caution is advised when considering dosage.
7. Donor evaluation:
*Important to know the age as Advanced age can increase the risk for perioperative complications,
*thorough history and physical examination laboratory testing, age-appropriate medical screening, renal imaging And any drug the donor is taking
*Evaluation of future risk
*and To exclude any Inherited Renal Disease as the primary disease of rthe receipient is unknown
Some studies results show that both rivaroxaban and apixaban are safe and efficient oral anticoagulant drugs in renal transplant patients. Additional studies are needed to prove these results.
Novel oral anticoagulants appear to be as effective in the renal transplantation population as in the general population. Also, we had a few bleeding events and no changes in renal function after the initiation of novel oral anticoagulants which suggests a good safety profile.
*Novel Oral Anticoagulants in Renal Transplant Recipients: A Retrospective Cohort Study
Nikolina Basic-Jukic 1, Vesna Furic-Cunko 1, Ivana Juric 1
Affiliations expand
PMID: 33011699
DOI: 10.2478/prilozi-2020-0032
Free article
*Efficacy and safety of non-vitamin K antagonist oral anticoagulants post-kidney transplantationMuhammad A Bukhari, Abdulrahman Al-Theaby, […], and Christine Ribic
Additional article information
*Handbook of Kidney Transplantation
Edited by
Gabriel M. Danovitch, MD
45 y old male end stage renal disease on regular haemodialysis with unknown his original kidney disease with history of DVT and PE.
currently treatment of DVT from three to six mouth but in some certain situation patient need life long anti-coagulant.
– unprovoked DVT .
-D-Dimer > 500 ng/ml.
-Extensive thrombosis involve multiple vein ( > 5 cm in length and 7 mm in a diameter)
-Thrombosis close to proximal vein
-persistent or irreversible risk factors ( active cancer).
-prior DVT or PE.
– prolonged immobility ( long stay ).
* eve must search for cause of primary kidney disease : autoimmune disease anti lupus anticoagulants and other thrombophilia screening ( antithrombin, protein c , protein a , lupus anticoagulant factor v Leiden, prothrombin gene mutation, anti-B-2-Glycoprotein-1 antibodies and anti-cardiolpin antibodies).
* in this patient we prefer life long anticoagulants.
– pre-operative operations withhold warfarin and shift to LMWH and whenINR > 1.5 we will proceed to operation and stop LMWH 24 H before operation and resume again 24-48 H after operation.
– inferior vena cava filter placement and thrombophilia screening.
-DOACs are safely used and in chronic kidney disease upto crcl < 30ml/m
dabigatran ( direct thrombin inhibitors ) apxiban and rivaroxiban factor card inhibitors
-they didn’t need follow up by INR.
– we can gave with renal dose adjustment and to be stopped 48 h before operation and to be started 24-48 H after surgery.
I will stop warfarin 5 days before transplant surgery and start low molecular weight5 heparin as he had history of PE. I will stop heparin day before surgery and upto 48 hours after surgery. again restart warfarin in his usual state according to INR.
2.Yes, if patient had history of recurrent PE despite anticoagulation, he needs IVC filter.
3.Newer anticoagulation has some advantages like need not to monitor INR. However, if bleeding occurs, there is no antidote. Heparin is preferable before surgery .
The first thing I would like to know whether this DVT and PE was provoked or unprovoked. If provoked anticoagulation is needed for atleast 6 months. If it was unprovoked obviously we need to work him up for thrombophilic disorders. In that case duration of anti coagulation will be extended and May be life long if PE was near fatal
He would require bridging with LMWH or unfractionated heparin during immediate post transplant period.
Recurrent PE despite anticoagulation makes it a very tough case. I would like to know if he was effectively anticoagulated or not?
IVC filter would be an option in such scenario
DAOC are considered safe in solid organ transplant and literature showing less bleeding episodes once compared with warfarin
Bridging heparin probably would not be needed due to their rapid onset of action
How do you manage this case?
We manage cases of DVT going ahead for kidney transplantation in similar way as explained by Prof. Halawa in his lecture. But my experience is limited in this case as we experience the issue of DVT with occasional PE in children with FSGS who have become CKD.
Even in these cases we give warfarin only for initial few weeks and then we shift patient to LMW. Hence, concept of bridging doesnt apply in these children as they are already on LMW.
Would your management differ if he had recurrent PE despite the anticoagulation?
my anticoagulation management would remain same as above the additional would be lung function assessment prior to transplant. there could be
V/Q mismatch
Increased alveolar dead space
over perfusion of normal lung tissue
High pulmonary pressures
All this can cause intra and post operative complications during anaesthesia and extubations which needs involvement of pulmonologist.
Would you manage him differently if he was on newer anticoagulation drugs called dabigatran, rivaroxaban and apixaban?
DOACs are safe and effective anticoagulants but not approved in pediatric population.
I would still consider following standard anticoagulation protocol in peri transplant period over DOAC because there is not adequate quality data of superiority of DOAC over traditional anticoagulation in peri transplant period